Chemokines are a group of proteins having migration activity for leukocytes and lymphocytes. From their structures, these chemokines can be divided roughly into four types. Those with the first and second cysteines arranged continuously are called “CC chemokines”.
Monocyte chemoattractant protein-1 (MCP-1), one of the CC chemokines, was reported as a protein by itself, and at substantially the same time, its cDNA sequence was ascertained (J. Exp. Med., 169, 1449-1459, 1989; J. Exp. Med., 169, 1485-1490, 1989; FEBS lett., 244, 487-493, 1989).
Receptors which recognize MCP-1 have already been identified, and their cDNAs have also been cloned (Proc. Natl. Acad. Sci. USA, 91, 2752-2756, 1994; Biochem. Biophys. Res. Commun., 202, 1156-1162, 1994). Nine types of receptors are now known as CC chemokine receptors, and the MCP-1 receptor is called “CCR2”.
Rollins et al. reported that they prepared a variety of amino acid mutants of MCP-1 protein and some of the amino acid mutants were found to have lost cell migration activity (J. Biol. Chem., 269, 15918-15924, 1994). Among these mutants, the mutant obtained by deleting the second to eighth amino acids as counted from the N terminal, that is, 7ND-MCP-1 has binding ability to CCR2, but does not provoke cell migration. As a dominant negative, on the other hand, 7ND-MCP-1 forms a dimer with wild-type MCP-1 and inhibits the function of MCP-1. Further, it is known that N-terminal deletions of chemokines are potent dominant negative inhibitors of chemokine-receptor interaction by forming heterodimers with the corresponding endogenous monomer of the chemokine and that these inhibitors are effective for the remedy of inflammations such as post-angioplasty restenosis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and chronic pulmonary inflammation, e.g., pulmonary fibrosis; autoimmune disease; and the like (JP-A-11506005).
Fibrosis of the liver is a morbidity in which destruction of the normal tissue structure, proliferation of fibroblasts and accumulation of extracellular matrices advance, and cirrhosis is a post-fibrosis disease. At present, no effective and safe remedial method has been established yet for these diseases. For example, various symptomatic treatments have been applied to cirrhosis, but cirrhosis advances to uncompensated cirrhosis, resulting in poor prognostic improvements.
An object of the present invention is to provide a novel preventive and/or remedy for a liver disease such as hepatic fibrosis or cirrhosis and further, a novel preventive and/or remedial method for such a liver disease.